Other Data Relevant to an Evaluation of Carcinogenicity and Its Mechanisms

WOOD DUST 173

3.5 Experimental data on wood shavings It has been suggested in several studies that cedar wood shavings, used as bedding for animaIs, are implicated in the prominent differences in the incidences of spontaneous liver and mammar tumours in mice, mainly of the C3H strain, maintained in different laboratories (Sabine et al., 1973; Sabine, 1975). Others (Heston, 1975) have attributed these variations in incidence to different conditions of animal maintenance, such as food consumption, infestation with ectoparasites and general condition of health, rather than to use of cedar shavings as bedding. Additional attempts to demonstrate carcinogenic properties of cedar shavings used as bedding materIal for mice of the C3H (Vlahakis, 1977) and SWJ/Jac (Jacobs & Dieter, 1978)

strains were not successful. ln no ne of these studies were there control groups not exposed to cedar shavings.

4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms

4.1 Deposition and clearance

4.1.1 Humans

No studies of the deposition of wood dust in human airways were available to the Working Group. Particle deposition in the airways has been the object of several studies (for reviews, see Brain & Valberg, 1979; Warheit, 1989). Large particles (? 10 ¡.m) are almost entirely deposited in the nose; the deposition of smaUer particles depends on size but also on flow rates and type of breathing (mouth or nose); there is also inter-individual variation (Technical Committee of the Inhalation Specialty Section, Society of T oxicology, 1987). Particles deposited in the nasal airways are removed by mucociliary transport (for reviews, see Proctor, 1982; Warheit, 1989).

4.1.2 Experimental systems No data on the deposition or clearance of wood dusts in animaIs were available to the W orking Group.

4.2 Toxic effects

4.2.1 Humans

(a) Effects on the nase ln a cross-sectional study in eight furniture factories in Denmark, 68 workers were exposed to total dust at concentrations? 5 mg/m3 in 63% of the measurements (Solgaard & Andersen, 1975; Andersen et al., 1977). The workers were exposed to a variety of hardwoods, including teak, and to pine and composites, including chipboard and Masonite. Analysis of particle size

,,;ç:.:,...:,...._-- 174 lARC MONOGRAPHS VOLUME 62

showed that 33% of the particles were .; 5 !-m. These workers had significantly lower nasal mucociliary transport rates than a group not exposed to dust; there was also a concentration- dependent decrease in the rates of the exposed workers: mucostasis was found in 63% of workers exposed to an average of25.5 mg/m3 and in 11% ofthose exposed to 2.2 mg/m3 (mean

concentration). Of ni ne subjects with mucostasis re-examined after 48 h with no exposure to wood, three still had mucostasis, while the six others had clearance rates within normal limits.

Middle-ear inflammation and common co Ids were more frequently reported by people exposed to concentrations:; 5 mg/m3 than among those exposed to lower levels. The nasal mucociliary transport-rate was investigated in nine woodworkers, 48-66 years of age, with 6-27 years of employment in the furniture industry in England (Black et al., 1974). They had slower rates than 12 people not exposed to wood dust. Only the worker with the shortest length of employment (six years) had a clearance rate within normal limits. Three workers had complete stasis. The results of cytological examination of nasal smears were reported only for the exposed workers: squamous cells were found in four workers, cuboidal ceUs in one and 'less mature basal ceUs' in another. Boysen and Solberg (1982) studied 103 workers in five Norwegian furniture factories in a cross-sectional study. The subjects constituted about 60% of workers who had been emp10yed for at least 16 years. Ten retired workers and 54 people without nasal disease or an occupation associated with nasal cancer, who were not employed In woodworking industries, were examined. Nasal biopsy samples taken from the middle turbinate showed metaplastic squamous epithelium in 40% of the furniture workers and 17% of controls; the cOITesponding figures for dysplasia were 12 and 2%, respectively. Mechanical processing of wood was associated with histological changes of the nasal mucosa. Dysplasia occuITed in four of 15 furniture workers

with exposure mainly to birch, spruce and pine and in nine of 84 exposed mai nI y to hardwoods. Nasal biopsy samples taken from the middle turbinate of 44 workers who had been exposed for 10-43 years to softwood dust but not to hardwood dust showed more changes than biopsy samples taken from age-matched men without nasal disease or an occupation associated with

nasal cancer (mean score, 2.0 vers us 1.4; p 0: 0.05) (Boysen et al., 1986). Four woodworkers and no control had dysplasia; these four men had been exposed for 20 years (one man) and more than 26 years (three men). Nasal symptoms were more frequent among the furniture workers (14% versus 4%; p 0: 0.05). Biopsy samples were taken from the nasal mucosa of the middle turbinate, at least 5 mm behind the anterior curvature, of 45 randomly selected workers in five furniture factories and one parquet flooring factory and 17 hospital workers in Sweden (Wilhemsson & Lundh, 1984). The mean length of exposure was 15 years (range, 1-39 years). Metaplastic cuboidal epithelium was significantly more prevalent among the woodworkers (26/45 versus 4/17; p .; 0.05), and columnar epithelium was significantly less frequent (34/45 versus 17/17; p .; 0.05). The prevalence of metaplastic squamous epithelium was not significantly increased (9/45 versus 4/17), and that of goblet-cell hyperplasia was somewhat more frequent (10/45 versus 1/17). Cuboidal metaplasia of the nasal mucosa was found in 19 of 22 cases of ethmoidal adenocarcinoma associated with exposure to wood dust in Sweden (Wilhemsson et al.,1985c). Histological examination of non-tumour nasal mucosa from 22 woodworkers with ethmoidal WOOD OUST 175 adenocarcinoma, who had been exposed to wood dust for an average of 38 years (range, 18- 55 years), showed cuboidal metaplasia in 19; 16 also had dysplasia. A transitional zone with dysplastic cuboidal epithelium in continuity with the tumour was observed in 10 cases. Squamous metaplasia was also seen in five cases, but there were no cases of squamous dysplasia. A cross-sectional study in Germany involved 149 male workers with at least 15 years' exposure to wood dust in different industries and 33 workers with no exposure to dust or chemicals (contraIs); people who had worked as farmers, welders or metal workers or were exposed to cement dust were excluded. CUITent exposure to wood dust varied between ~ 1 mg/m3 and ? 5 mg/m3. Mucociliary clearance was not significantly different in workers exposed to unprocessed woods (oak, beech and softwood) and controls. Woodworkers with concomitant exposure to formaldehyde or chromium had decreased clearances (p = 0.04 and 0.01, respecti vely), and workers exposed to particle-board had slower mucociliary clearance. The findings in nasal biopsy samples taken from the middle turbinate were reported for various single ceU types (columnar-cell hyperplasia, squamous-ceU metaplasia, cuboid metaplasia) and mixed cell types (Wolf et al., 1994). (The Working Group noted the inadequate reporting of the histological classification and the high prevalence of squamous epithelial metaplasia in the control group. The Group analysed the data according to hyperplasia and metaplasia in single ceU types and found no significant differences between woodworkers and contraIs (Table 32). The odds ratios for woodworkers exposed to softwood or hardwood, but no additives, were 2.2 (95% CI, 0.81-6.2) for cuboid metaplasia, 0.40 (0.16-1.0) for squamous-cell metaplasia and 1.3 (0.47-3.5) for columnar-cell hyperplasia. Cuboid metaplasia was commoner in workers exposed to hardwood (3.5; 1.1-12), softwood (3.1; 0.77-12) or particle-board (25; 0.70-8.8) without additives than in controls but was significant only for workers exposed to hardwood.) ln a cross-sectional study of workers in furniture factories in Sweden who were exposed to formaldehyde alone and to formaldehyde plus wood dust, nasal discomfort was more frequent than in clerks (Holmström & Wilhemsson, 1988). The mean combined exposure to wood dust was 1.7 mg/m3 and that to formaldehyde was 0.25 mg/m3; however, the prevalence of symptoms was similar in workers exposed to formaldehyde alone (mean concentration, 0.26 mg/m\ Impaired mucociliar clearance in the nose was seen in 15% of the group exposed to wood dust plus formaldehyde, in 3% of controls and in 20% of those exposed to formaldehyde alone exposure (p ~ 0.05). Workers exposed to formaldehyde alone or to formaldehyde plus wood dust had significantly (p ~ 0.01) decreased sensitivity in an olfactory test in comparison with controls. Marked histological changes were seen in the nasal mucosa of 25% of people exposed only to formaldehyde (score, 2.2; p ~ 0.05), but the difference between those exposed to both formaldehyde and wood dust (64% (p ~ 0.01); score, 2.1) and the controls (53% (p ~ 0.01; score, 1.6) was not significant. No correlation was found between histological score and either duration or concentration of exposure (Holmström et al., 1989b). A total of 676 workers in 50 Swedish furniture factories were classified according to exposure to wood dust as 'heavily/moderately' or 'slightly/non-exposed' (Wilhemsson & Drettner, 1984) (the details of the classification were not reported). Nasal hypersecretion (20%

";.,..,~':",,,.',~ , _.~... Table 32. Frequency of histological findings in nasal biopsy sam -i pies from German woodworkers according to exposure 0'

Type of Additives. No.b Histological finding wood

Columnar- Squamous Cuboid Columnar Columnar Squamous Any Any Any cuboid Normal Dysplasia cel! metaplasia metaplasia hyperplasia, hyperplasia, metaplasia, columnar squamous metaplasia hyperplasia (2) (3) squamous cuboid cuboid hyperplasia metaplasia (3+5+6)" (1) (4) (5) (6) (1+4+5)" (2+4+6)"

Hardwood No 31 6 1 5 3 1 6 10 10 12 9 3

Softood No 17 2 1 4 2 1 1 8 4 6 6 0

Paric1e- No 26 5 5 4 4 3 1 13 10 8 4 0 board -- Softood Yes 19 3 9 3 2 1 0 6 II 4 ~ Hardwood Yes 21 7 ;; 4 2 2 1 1 10 7 4 4 1 \. Mixed Yes 30 9 5 3 7 0 3 16 15 6 3 2 3: - 0 Controls 33 2 12 3 3 3 i 6 14 5 9 1 0Z From Wolf et al. (1994) 0 . Glues, soivents, etc. :; b The Working Group noted that the total numbers ofmen and findings were different, indicating that some people were not biopsied. 'i~ C Calculated by the Working Group :: C/ 0~ c:r 3: t1 l'0\ WOOD DUST 177

versus 12%; p .- 0.05), obstruction (40% vers us 30%; p .- 0.05) and more than two common colds per year (21 % vers us 9%; p .- 0.05) were reported more often in subjects with heavy/- moderate exposure than in the other group. A cross-sectional study was conducted of LOI woodworkers and 73 people not exposed to dust in Germany. The concentrations of dust were measured for each of the men (method of sampling was not reported): 14 were exposed to .- 5 mg/m3, 15 to 5-9 mg/m3, 36 to 10- 19 mg/m3 and 36 to 2: 20 mg/m3. An increased frequency of hyperplasia and reddening of the nasal mucosa was seen in the exposed workers (50-86% vers us 7% in controls) (Ruppe, 1973). Radiographic signs of sinusitis were found in 25% of the woodworkers and 5% of controls. Cough, with or without phlegm (50% versus 11%), and conjunctivitis (15% versus 0%) were also reported more frequently among the exposed workers (significance values not reported). ln a cross-sectional study of the frequency of pulmonary and nasal symptoms in 168 woodworkers and 298 workers with no significant exposure to wood dust in furniture factories in South Australia (PisanieUo et al., 1992), the mean concentration of hardwood dust was 3.8 mg/m3, and the mean concentration of softwood dust produced by machining particle-board and medium-density fibre-board was 3.3 mg/m3. There was a significant association (odds ratio, 2.2; 95% CI, 1.2-4.2) between exposure to hardwood dust and two or more nasal symptoms, after adjustment for smoking and age. ln a cross-sectional study, Goldsmith and Shy (1988) examined 55 people exposed to hardwood dust in the furniture industry in the United States. The mean length of employment in this industry was 16.6 years, and the current concentration of dust was s 2 mg/m3. Frequent sneezing and eye irritation were commoner in these workers than in workers with no exposure to wood dust or finishes (prevalence odds ratios, 4.1 and 4.0; p.- 0.05) in an analysis with adjustment for age, sex and smoking habits. Significant differences were reported for nasal

obstruction (61 % vers us 21 %), nasal discharge (41 % versus 13 %) and sneezing (77% versus 32%). Symptoms in the upper and lower airways were reported more frequently among 44 randomly selected woodworkers, exposed to concentrations of 1.0-24.5 mg/m3 dust, than among 38 office workers examined in a cross-sectional study in New Zealand (Norrish et al., 1992). The effects of exposure to wood dust on the nose are summarized in Table 33.

(b) Effects on the lung There are several case reports of asthma due to exposure to wood dust (for reviews, see Kadlec & Hanslian, 1983; Goldsmith & Shy, 1988). The asthmatic responses to western red cedar (Chan- Yeung, 1982, 1994) and eastern white cedar (Cartier et aL., 1986) are elicited by plicatic acid. Cough (odds ratio, 2.2; p .- 0.001), dyspnoea (2.5; p .- 0.001) and asthma (2.7; p .- 0.001) were reported more frequently among 652 western red cedar miU workers than among 440 office workers in a cross-sectional study in Canada (Chan- Yeung et al., 1984). Impairment of pulmonary function, as measured by forced expiratory volume in 1 sec (FEV 1), forced vital capacity (FVC), forced mid-expiratory flow between 25 and 75% of FVC (FEF25-75%) and

~~.. Table 33. Effects (other than cancer) of exposure to wood dust on the nose -- 00

Study population Geographical Industi Wood type Dust Paricle size, Period of Nasal effects Reference area concentration characteristic exposure in air (mg/m') (years) Exposed Controls Nasal Effect (age, (age, region years) years)

68 men 66 men Denmark, Eight wood- Teak, oak, '" 5 in 63 % of 5-10 ¡i 1-51; Mucostasis: 15% in controls, 38% in Solgaad & (17-66) Aarhus working factories chipboard, measure- maximum mean, 16 exposed, 63% in exposed with dust Andersen county palisander and ments "IOmg/m'(n=17) (1975); other woods Andersen e/ aL. (1977)

9 12 England, One wood- 6-27 Mucociliar clearance of polystyrene Black e/ al. (48-66) (31.69) High working factory paricles in controls, 6.8 (1.9-18.5) (1974) - Wycome area mm/min. Mucostasis in 7/9 exposed. ~ III workers, nasal mucosa was normal :; columnar (3); normal + squamous cells n (1); normal + cuboidal (1); normal + ~ squamous metaplasia (3); normal + less 0 mature 'basal' cells (1). Results for Z con troIs not given a0 103 active 54 Norway, Five fumiture Birch, beech, Active, Anterior Rhitioscopy: hyperplastic rhinitis: Boysen & (32-69); (35-79) westem factories oak, pine, 16-57; curvature 5 controls, 37 workers (p 0( 0.05); Solberg (1982) ~ 10 retired malogany, teak, mean, 34; of middle mucosal polyps: 1 controls, 3 workers "" His/ological score: control :: (68-81) chipboard (made retired, turbinate s, 1.5; all v: of pine and 28-57; workers, 2.4 (p 0( 0.05); active workers, ~ spruce) mean, 44 2.4; retired workers, 2.9 0 44 37 men Norway Six fumiture Exclusively 10-43; Anterior His/ological score Boysen el al. L" (29-64) (35-66) factories softood mean, 24 curvature Controls W orkers (1986) c: of middle Ali 1.4 2.0 (p 0( 0.05) ~ turbinate Age" 44 1.2 1.6 tn Age 44-54 1.4 2.4 0\ N Age" 55 1.6 1.9 Smokers 1.6 2.4 (p 0( 0.05) Non-smokers 1. 1.6

45 (mean, 17 (mean, Sweden, Five fumiture 0.3-5.1; 1-39; Middle Columnar epithelium: Wilhelmsson & 40) 39) Smâland factories mean, 2.0 mean, 15 turbinate 14/17 controls, 23/45. workers Lundh (1984) county in widest ciliated: 12/1 7 controls, 16/45 workers nasal (p 0( 0.05); cavity unciliated, 2/1 7 controls, 7145 workers; Cuboidal epithelial metaplasia, 1/17 controls, 16/45 workcrs (p 0( 0.05) Squamous epithelial metaplasia, 2/17 controls; 6/45 workers Table 33 (contd)

Srudy population Geographical InduslI Wood type Dust Paricle size, Period of Nasal effects Reference area concentration characteristic exposure in air (mg/m') (years) Exposed Controls Nasal Effect (age, (age, region years) years)

22 men Sweden 14 fumiture 18-55; 19 cases of cuboidal metaplasia, 16 with with Wilhelmsson makers, mean, 38 dysplasia ethmoidal et al. (1985c) 3 french polishers, 10 cases of transitional zone with adeno- 2 boat builders, dysplastic cuboidal epithelium ¡n carcinoma 2 wood continuity with the rumour (57-86) machinists, 5 cases of squamous metap1asia 1 woodwork teacher

100 36 Sweden Fumirure workers Paricle-board Wood, 82%'" 5 fl 1-30; Nasal discomfort: 6 controls, 53 wood Ho1mström & exposed to (mean, 1.65,"1.06; mean, 9 + HCHO, 45 HCHO; Wilhelmsson wood dust 39.7) HCHO, eye discomfort: 2 controls, 21 wood + and (1988) 0.25,"0.05 HCHO, 17 HCHO; HCHO deep airway discomfort: 5 control, 39 ~ (mean, wood + HCHO, 31 HCHO; 0 40.5) 0 frequent headache: 2 control, 17 wood + V Chemical plant 0.05-D.5 1-36; HCHO, 17 HCHO 70 mean, 0 exposed to c: 10A í/ HCHO -- (mean, 36.0)

89 32 Sweden F umi rure workers Paricle-board Wood, 82%'" 5 fl 1-30; Median Nasal biopsy scores: Holmström exposed to 1.6h1.06; mean, 9 or control, 1.56; et al. (1989b) wood dust HCHO, inferior wood + HCHO, 2.07; and 0.25,"0.05 aspect of HCHO, 2.16 (p '" 0.05) HCHO middle rurbinate 62 Chemical plant 0.05-D.5 1-36; exposed to mean, HCHO 10A 484 with 192 with Sweden, 50 furni rure Mean, 2.0; 1-60; Nasal hypersecretion: Wi1helmsson & heavy or light or no Smâland factories range, 0.30- mean, 27 12% light or no exposure Drettner (1984) moderate exposure county 5.06 20% moderatelheavy exposure exposure Nasal obstruction: 30% light or no exposure 40% moderatelheavy exposure - \0-. 0- 000 Table 33 (contd)

Study population Geographical Industr Wood type Oust Pariele size, Period of Nasal effects Reference area concentration charcteristic exposure in air (mg/m 1) (years) Exposed Controls Nasal Effec! (age, (age, region years) year )

101 73 Gennany ;; 5-;0 20 Sneezing: Ruppe (1973) (18-65) (18-65) 0/73 controls 7/140(5 mg/ml 111155-9 mg/ml 32/3610-19 mg/ml - 30/36 ;0 20 mg/ml ;¡ Mucosal changes: ~ 5/73 controls n 7/140(5 mg/ml 8/15 5-9 mg/ml ~ 31/3610-19 mg/ml Ž 25/36 ;0 20 mg/ml 0 134 298 South 15 fuiture Oak, teak, Hardwood Two or more nasal symptoms (out of five): Pisaniello el al. a exposure to hardwood dust, odds ratio, ~ . (mean, (mean, Ausirlia factories nyardoh, radiase dust, 3.2; (1992) ;¡ 33.6) 40.1) pine, pariele' pariele-board, 2.2 (1.-4.2) "t board, fibre' fibre-board, :: board 3.3 v:

149 men 33 Gennany W oodworkers Oak, beech, 0( 1-:: 5 ;0 15 Middle Mucociliar elearance longer in workers Wolf et aL. ~ turbinate exposed to pariele-board dust (:: 35) softood. (1993) 0 pariele,board Columnar-cell hyperplasia: ail wood l' workers versus contrais, odds ratio, c: 4.4 (p = 0.05) ~ tT Squamous-cell metaplasia: woodworkers 0\ vers us controls, odds ratio, 0.37 IV (p = 0,02) Cuboid metaplasia: ail woodworkers versus controls, odds ratio, 2.9 (p = 0.3) i: f1 1

Table 33 (contd)

Study population Geogrphical IndustI Wood type Dust Pari cie size, Penod of Nasal effects Reference area concentrtion charctenstic exposure in air (mg/ml) (years) Exposed Con troIs Nasal Effect (age, (age, region year ) years)

44 men 12 men USA, Nort One fuiture Hardwoods, Men. Frequent sneezing; odds ratio, 4.1 Goldsmith & Carolina factory (mean, (mean, fibre,board mean, (1.-15) Shy (1988) 47.2) 42.2) 18.5; i i women 4 women women, (mean, (mean, mean, 9 41.) 44.5) and 7 men and 14 women in a finishing deparent 44 men 38 men New Zealand i i fuiture and Rimu wood, 1 -25.4 Nasal obstrction: 27/44 versus 8/38, Norrsh el aL. :E (mean, (mean, 33) joinery facilities kaur, tawa, p '" 0.01 (1992) 0 33) mediur-density Nasal discharge: 12/44 versus 5/38, 0 fibre, Califomian p"'O.OI 0 red woo Sneezing: 34/44 versus 12/38,p '" 0.01 0 r:c: 'p '" 0.05 -i

00 182 IARC MONOGRAPHS VOLUME 62

FEV ¡lFVC, was significantly correlated (p 0: 0.001) with increasing length of employment in cedar miUs. The odds ratios were adjusted for smoking, race and age. Occupational asthma was diagnosed in 10 of 73 workers exposed to red cedar dust in a cross-sectional investigation in the United States, which also included 132 mill workers and 22 clerks and engineers not exposed to wood dust (Brooks et al., 1981). The mean concentration of total dust was 4.7 mg/m3. Pulmonary diseases (chronic bronchitis, occupational asthma, chronic nonspecific airways disease and non-occupational asthma) were commoner among the workers than among contraIs (34% versus 16%) (p value not reported). The preva1ence of chronic bronchitis in workers exposed to a mixture of woods, mainly Douglas fir, West Coast hemlock and red aIder, was similar to that of the workers exposed to western red cedar.

ln the study of Norrish et al. (1992), described on p. 177, differences were reported for persistent cough in winter (30% vers us 5%; pO: 0.01) and work-related cough (32% versus 0%; pO: 0.01). Five woodworkers were identified as having occupational asthma. The authors stated that adjustment for smoking did not alter the results. ln a cohort study based on census data on occupational title in Sweden, the rate of mortality from asthma was greater in woodworking machine operators (SMR, 2.3; 95% Ci, 1.1-3.4), after adjustment for smoking (Torén et al., 1991). Ávila (1972) reported on 23 Portuguese cork workers with bronchia1 asthma, aU of whom gave positive responses in inhalation tests for immediate and late reactions to a skin prick with cork. A further 12 cork workers with diseases affecting mainly peripheral gas-exchange tissues aIl gave positive responses in skin tests for late (type Ill, arthris) reaction to cork; the y showed diffuse, fine miliary mottling on chest radiographs, which disappeared within five weeks, except in a few cases where les ions attributable to fibrosis were reported. (The Working Group noted the lack of information on examination procedures). The exposure of 334 workers to total dust was determined from job title and job location in a cross-sectional study in Canada (Vedal et al., 1986). The workers were exposed mainly to wood dust from western red cedar. ln 78 samples, the total dust concentration ranged from undetectable to 6.0 mg/m3, with a mean of 0.46 mg/m3; 33 workers were considered to be exposed to ? 1.0 mg/m3. Spirometric measurements (FVC and FEV1) gave lower values (p 0: 0.05) for 13 men exposed to concentrations? 2.0 mg/m3; chronic cough, dyspnoea, persistent wheeze and asthma were not related to duration of work or dust concentration. Al Zuhair et al. (1981) studied workers in two furniture factories in the United Kingdom. ln the first factory, 53 workers in a sawmill and an assembly deparment were exposed to dust concentrations of 2.9 and 0.5 mg/m3, respectively. ln the second factory, 60 workers on a machine floor and in a cabinet shop were exposed to mean total dust concentrations of 1.4 and 8.3 mg/m3, respectively. These workers had significantly decreased FEV1 and FVC over the workshift period (0.08-0.12 L; p 0: 0.001), while there was no consistent decrease in lung fuction over the workshift period among workers in the first factory. Pulmonar fuction (FVC, FEV b FEV ¡lFVC and maximal mid-expiratory flow (MMEF; identical to FEF25-75%D was determined in 1151 subjects exposed to maple or pine wood dust in a crass-sectional surey in the United States (Whitehead et aL., 1981 b). Suspended dust concen- WOOD DUST 183 trations were measured in area samples, and a cumulative index of the dose was constructed for each person by multiplying the concentration in the job area by the working time. The workers were classified as having low (0-2 mg-years/m\ medium (2-10 mg-years/m3) or high (10 or more mg-years/m3) exposure to wood dust. The authors c1assified the results of the spirometric tests as 'normal' or 'impaired' on the basis of extemal reference values and calculated the odds ratios between different categories of exposure. The ratio for FVC or FEV 1 was not significantly increased with increasing levels of exposure in the groups exposed to maple or pine wood, but FEV ¡/FVC and MMEF were lower in people with high exposure. ln a comparison of high and low exposure categories, the odds ratios for FEV¡!FVC and MMEF were 3.1 (p = 0.01) and 2.1 (p = 0.02) for workers exposed to maple dust and 4.0 (p = 0.01) and 2.5 (p = 0.02) for workers exposed to pine dust, after adjustment for smoking. ln a study of 145 nonsmoking furniture workers and 152 nonsmoking workers in a bottling firm with no exposure to dust in South Africa, cough (40.6% versus 23.7%; p .. 0.01), phlegm

(4.1% versus 10.5%; p .. 0.05), dyspnoea (18.7% vers us 5.7%; p .. 0.05), wheezing (12.8% versus 4.8%; p .. 0.05) and nasal symptoms (49.5% vers us 18.7%; p .. 0.01) were two to three times commoner in exposed than unexposed workers (Shamssain, 1992). Spirometric measurements were significantly lower for exposed men than for male controls (FVC: 3.64 versus 4.14 L, p .. 0.001; FEV¡: 2.65 versus 3.20 L, p .. 0.001; FEV¡!FVe: 73.2 versus 77.6%, p.. 0.01; forced mid-expiratory flow between 25 and 75% of FVC (FMF25-75%J: 3.09 versus 3.68 Lis, p .. 0.01; forced expiratory flow between the first 200 and 1200 ml of FVC

(FEF200-12ooJ: 4.94 vers us 7.06 Lls,p.. 0.001; peak expiratory flow (PEF), 6.14 versus 7.92 Lis, p.. 0.001); there was no significant difference in these measurements between exposed and unexposed women. The frequency of an FEV¡!FVC below 70% was significantly higher among the woodworkers than the controls (30% versus 17%, p .. 0.01), and the proportion was higher in men with 10-19 years of employment than in men with 1-9 years of employment (56% vers us 27%, p .. 0.01); 20% of the workers handled pine wood and 80% medium-density fibre-board. The mean total dust concentration in the factory was 3.8 mg/m3. ln the study of Goldsmith and Shy (1988), described on p. 177, peak flow (but no other test of pulmonar function) was correlated with duration in jobs with exposure to wood dust. The decrease in lung function over a work shift was greater in 50 carpenters and joiners than in 49 hospital workers (Holness et al., 1985). The decreases in FVC were 2.4 (p = 0.001) and 0.15% (p = 0.77), respectively. The mean total dust concentration was 1.8 mg/m3.

(c) Other effects Exposure to wood may cause irrtant dermatitis, contact urticaria and allergic contact dermatitis (for reviews, see Woods & Calnan, 1976; Hausen, 1986). The contact aUergens in a

number of woods have been identified, e.g. R-3,4-dimethoxydalbergione was found in a tropical hardwood, Machaerium scleroxylum (Beck et al., 1984). AUergic conjunctivitis was reported in a worker exposed to spindle tree dust (Herold et al., 1991). Of 162 patients with a positive response in a skin prick test to one of 14 woods, 107 had no aUergic symptoms (Oehling, 1963).

,¿;..;,~ ".. -- 184 lARC MONOGRAPHS VOLUME 62

Inhalation fever and extrinsic aUergic alveolitis have been observed in studies of workers exposed to wood contaminated with mou Ids (Emanuel et al., 1962; Belin, 1987; Dykewicz et al., 1988).

4.2.2 Experimental systems A mouse hepatoma ceUline, Hepa-1, was used to study cytotoxicity (effect on ceU growth) and induction of enzymes (cytochrome P450IA1 and aldehyde dehydrogenase). The cells were exposed for 24 h to acetone extracts (final concentration of acetone, 0.5%) of bleached cellulose materials, softwoods (pine and a mixture of pine and spruce) and hardwoods (aIder and aspen), aU of which are used as bedding materials in cages for smaU laboratory animaIs. The softwood and aIder extracts (final concentrations corresponding to 1.25-5 mg bedding material/ml ceU culture medium) were more cytotoxic to the hepatoma cells than the aspen extract, whereas the bleached cellulose materials were found to be nontoxic at doses up to and including 20 mg/mL. Both softwood and hardwood extracts induced the activity of cytochrome P450IA1 and aldehyde dehydrogenase at concentrations which caused little toxicity (Törrönen et al., 1989). ln order to investigate the toxicity of plicatic and abietic acids, which are constituents of Western red cedar and pine woods, respectively, primary cultures of rat type II ceUs (isolated from Sprague-Dawley rats (sex unspecified)) and ofhuman lung carcinoma cellline A549 were exposed to solutions of up to 1 mg/ml abietic acid and 5 mg/ml plicatic acid for 2-24 h. A time- and dose-dependent induction of cell lysis was seen with both cell types. Abietic acid was significantly more toxic (first observable effect after 2 h at 0.1 mg/ml) than plicatic acid (first effect after 4 h at 2.5 mg/ml). ln studies with cultured tracheal explants from Sprague-Dawley rats (sex unspecified), both compounds produced dose-dependent desquamation of epithelial ceUs, abietic acid again having a higher toxic potential than plicatic acid (Ayars et al., 1989). ln order to assess the tumorigenic effect of the combination of beech wood dust and formaldehyde (see also section 3.1), groups of 16 female Sprague-Dawley rats (11 weeks old) were exposed by inhalation in who le-body exposure chambers to freshly prepared wood dust (70% with a longest dimension of about 10 /-m, 10-20% :: 5 ¡.m) at 25 mg/m3 for 6 h per day on five days per week for 104 weeks, with or without formaldehyde. There was also an untreated control group. AnimaIs were exposed in an inversed 24-h cycle, which ensured that they were as active as possible during exposure. Apart from neoplastic and preneoplastic lesions (see section 3.1), histopathological evaluation showed a greater prevalence of pulmonary emphysema in rats exposed to wood dust than in the control animaIs (p .c 0.05), but no differences in mortality rates and no significant difference in the histological appearance of pulmonar epithelium were observed (Holmström, et aL., 1989a). ln a study to assess the tumorigenic effects of a combination of beech wood dust and NDEA (see also section 3.1), groups of 19-23 male Syrian hamsters, weighing 90-120 g, received either wood dust or NDEA alone or the combination The animaIs were exposed by inhalation in whole-body exposure chambers to particles of fresh beech wood dust (30 mg/m3) for 6 h per day on five days per week over a period of 40 weeks. ln the group of hamsters exposed to wood dust alone, slight inflammatory reactions of the respiratory epithelium and WOOD DUST 185 submucosal stroma were detected, which were not observed in the respective control animaIs (Wilhemsson et al., 1985a,b). Sixteen male guinea-pigs weighing about 300 g were given a single intratracheal instillation of 75 mg of sheesham or mango wood dust as an autoclaved suspension. AnimaIs were killed 60 and 90 days after treatment. Treatment induced disintegration of giant cells, centrilobular emphysema and slight fibrosis in the lungs at both times (Bhattacharjee et al., 1979). The enzyme induction activity of shavings from Eastern red cedar and oil of cedarwood was studied indirectly in groups of6-18 C3H-A, CBAlJ and Swiss albino mice (sex unspecified) as barbiturate sleeping time, the tIme between loss and restoration of the righting reflex after intraperitoneal injection of hexobarbital at 125 mg/kg bw). ln five separate experiments in which mice were reared and/or housed with cedar bedding material for at least three weeks, a reduction in sleeping time (p ~ 0.01) was seen, which was attributed to the induction of enzymes responsible for hexobarbital oxidation (Sabine, 1975).

4.3 Genetic and related effects

4.3.1 Humans Chromosomal aberrations in peripheral lymphocytes were studied in 13 male nonsmokers employed in three plywood factories in Finland, who were reported to be exposed to fumes emitted from heated wood. The controls were 15 male nonsmokers matched for age but not employed in wood industries. The frequency of chromatid breaks was 2.1 % in the exposed group and 1.0% in the controls (p ~ 0.01) (Kurttio et al., 1993). (The Working Group noted that exposure to wood dust was not mentioned.)

4.3.2 Experimental systems Extracts of certain woods prepared by a variety of methods (see Table 34 and section 1.3.2) gave weak positive or borderline effects for reverse mutation in Salmonella typhimurium.

Une qui vocal positive results have been obtained only with beech wood (Mohtashamipur et al., 1986); however, other woods have not been examined to the same extent. (The Working Group noted that wood contains constituents that can reduce the activity of mutagens such as benzo( a)- pyrene, aflatoxin Bi and methylmethane sulfonate.) ChemicaUy and bacterially degraded beech wood lignin significantly induced reverse mutation in S. typhimurium (Mohtashamipur & Norpoth, 1990), but fumes produced during the drying of birch and spruce wood were not mutagenic to S. typhimurium (Kurttio et al., 1990). (The Working Group noted the inappropriate correction for cell survival applied by the authors, which resulted in a different conclusion.) Cyclohexane-ethanol extracts of beech, oak and particle-board increased the number of DNA single-strand breaks per fragile sites in rat hepatocytes in vitro (Schrezer et al., 1994). Alcoholic extracts of beech wood increased the frequency of micronuclei in the crypts of the small intestine of mice treated by gavage and in the nasal epithelium of rats after topical application (Nelson et al., 1993). Of several compounds isolated from wood, only quercetin and /13 -carene showed mutagenic activity (Table 35).

~'-.. 00 0\

Table 34. Genetic and related effects of wood dusts

Test system Resulta Extraction medium Reference

Without With exogenous exogenous metabolic metabolic system system

Ash ?.. SAO, Salmonella typhimurium TAI 00, reverse mutation (+) (+) Methanol McGregor (1982) :: C1 Beech 2: SAO, Salmonella typhimurium TAI 00, reverse mutation (+) 0 Methanol; Brockmeier & Norpoth (1981) 0 cyclohexane/water 0Z SAO, Salmonella typhimurium TAI 00, reverse mutation 0 (+) Methanol Mohtashamipur et al. (1984) C) SAO, Salmonella typhimurium TA100, reverse mutation - - Acetone/water Kubel et al. (1988) ~ SAO, Salmonella typhimurium TAI 00, reverse mutation 0 + MethanoVethyl acetate Mohtashamipur et al. (1986) "' :: SAO, Salmonella typhimurium TAI 00, reverse mutation 0 + Acetone/water; lignin Mohtashamipur & Norpoth C/ degradation (1990) ~ - 0 SA9, Salmonella typhimurium TA98, reverse mutation (+) Methanol McGregor (1982) l' SA9, Salmonella typhimurium TA98, reverse mutation - - Acetone/water Kubel et al. (1988) c: DIA, DNA strand breaks, rat hepatocytes in vitro Cyclohexane/ethanol Schmezer et al. (1994) 2: (+) t1 MVM, Micronucleus induction, mouse duodenal crypts in vivo + MethanoVethy1 acetate Mohtashamipur & Norpoth 0\ (1989) N MVR, Micronucleus induction, rat nasal epitheliai cells in vivo + Methanol/ethyl acetate Nelson et al. (1993) Birch SAO, Salmonella typhimurium TA100, reverse mutation - - Drying fumes Kurtio et al. (1990) Chestnut SAO, Salmonella typhimurium TAIOO, reverse mutation - - Acetone/water Weissman et al. (1989) SA9, Salmonella typhimurium TA98, reverse mutation - - Acetone/water Weissmann et al. (1989) Elm SAO, Salmonella typhimurium TAIOO, reverse mutation - - Methanol Mc Gregor (1982) Table 34 (contd)

Test system Resulta Extraction medium Reference

Without With exogenous exogenous metabolic metabolic system system

Limba, obeche and walnut SAD, Salmonella typhimurium TAI 00, reverse mutation (+) 0 Methanol; Brockmeier & Norpoth (1981) cyclohexane/water SA9, Salmonella typhimurium TA98, reverse mutation (+) 0 Methanol; Brockmeier & Norpoth (1981) cyclohexane/water Mahogany ~ SAD, Salmonella typhimurium TAI 00, reverse mutation - - Methanol; Brockmeier & Norpoth (1981) 0 cyclohexane/water 0 SAD, Salmonella typhimurium TAI00, reverse mutation - - Methanol McGregor (1982) 0 - - c: SA9, Salmonella typhimurium TA98, reverse mutation Methanol; Brockmeier & Norpoth (1981) C/ cyclohexane/water -i Oak SAD, Salmonella typhimurium TAI 00, reverse mutation (+) 0 Methanol; Brockmeier & Norpoth (1981) cyclohexane/water SAO, Salmonella typhimurium TAI 00, reverse mutation - - Methanol McGregor (1982) SAD, Salmonella typhimurium TAI 00, reverse mutation - - Acetone/water Weissmann et al. (1989) SA9, Salmonella typhimurium TA98, reverse mutation (+) 0 Methanol; Brockmeier & Norpoth (1981) cyc1ohexane/water SA9, Salmonella typhimurium TA98, reverse mutation - - Acetone/water Weissmann et al. (1989) DIA, DNA strand breaks, rat hepatocytes in vitro + Cyclohexane/ethanol Schmezer et al. (1994) Spruce SAO, Salmonella typhimurium TAI 00, reverse mutation - - Acetone/water Kubel et al. (1988) SAO, Salmonella typhimurium TAI 00, reverse mutation - - Drying fumes Kurtio et al. (1990) - SA2, Salmonella typhimurium TA 102, reverse mutation - Drying fumes Kurtio et al. (1990) SA9, Salmonella typhimurium TA98, reverse mutation - - Acetone/water Kubel et al. (1988) - 00-- 00 00

Table 34 (contd)

Test system Resulta Extraction medium Reference ;; n~ Without With ~ exogenous exogenous zo metabolic metabolic o system system CJ ~ "' Spruce (contd) :: SA9, Salmonella typhimurium T A98, reverse mutation Drying fumes Kurtio et al. (1990) C/ ~ DIA, DNA strand breaks, rat hepatocytes In vitro Cyc1ohexane/ethanol Schmezer el al. (1994) o r- Particle-board C DIA, DNA strand breaks, rat hepatocytes in vitro + Cyc1ohexane/ethanol ~ Schmezer et al. (1994) tT 0\ 0+, considered to be positive; (+), considered to be weakly positive in an adequate study; ., considered to be negative; 7, considered to be inconc1usive N (variable responses in several experiments within an adequate study); 0, not tested Table 35. Genetic and related effects of wood-related compounds

Test system Resulta Reference

Without With exogenous exogenous metabolic metabolic system system

,13-Carene SAO, Salmonella typhimurium TA 1 00, reverse mutation (+) Kurtio et al. (1990) SA2, Salmonella typhimurium TA 1 02, reverse mutation Kurtio et al. (199O) SA9, Salmonella typhimurium TA98, reverse mutation (+) Kurtio et al. (1990)

Coniferyl alcohol SAO, Salmonella typhimurium TA 1 00, reverse mutation Mohtashamipur & Norpoth (1984) SA9, Salmonella typhimurium TA98, reverse mutation Mohtashamipur & Norpoth (1984) 0~ 0 Deoxypodophyllotoxin Û SAO, Salmonella typhimurium TA100, reverse mutation Mohtashamipur & Norpoth (1984) Û SA9, Salmonella typhimurium T A98, reverse mutation c: Mohtashamipur & Norpoth (1984) ..C/ 2,6- Dimethoxybenzoq uinone SAO, Salmonella typhimurium TA 1 00, reverse mutation Mohtashamipur & Norpoth (1984) SA9, Salmonella typhimurium TA98, reverse mutation Mohtashamipur & Norpoth (1984) Eugenol SAO, Salmonella typhimurium TAIOO, reverse mutation lARC (1985a) Quercetin SAO, Salmonella typhimurium TAlOO, reverse mutation o + Bje1danes & Chang (1977) SA8, Salmonella typhimurium TA1538, reverse mutation ° (+) Bjeldanes & Chang (1977) SA9, Salmonella typhimurium TA98, reverse mutation ° + Bjeldanes & Chang (1977) Scopoletin SAO, Salmonella typhimurium TAlOO, reverse mutation Mohtashamipur & Norpoth (1984) SA9, Salmonella typhimurium TA98, reverse mutation Mohtashamipur & Norpoth (1984)

00- \D \0 Table 35 (contd) o

Test system Resulta Reference

Without With exogenous exogenous metabolic metabolIc system system

3,4,5- Trimethoxycinnamic acid SAO, Salmonella typhimurium TA 1 00, reverse mutation Moht;:shamipur & Norpoth (1984) SA9, Salmonella typhimurium TA98, reverse mutation Mohtashamipur & Norpoth (1984) ;; ;; Vanilic acid () SAO, Salmonella typhimurium TA 1 00, reverse mutation Mohtashamipur & Norpoth (1984) ~ SA9, Salmonella typhimurium TA98, reverse mutation Mohtashamipur & Norpoth (1984) o oz a+, considered to be positive; (+), considered to be weakly positive in an adequate study; -, considered to be negative; ?, considered to be Ci ~ inconc1usive (variable responses in several experiments within an adequate study); 0, not tested "0 r::: .. o t" c: ~ tn 0' N